Peptides were synthesized that were expected to interact with specific structural and/or functional domains of the homo-dimeric 99 residue long HIV protease, and in this manner exert inhibitory activities. Design strategy utilized the generation of anti-sense peptides with optimized hydropathic anticomplementarity to the native sequences. For comparison the DNA based anti-sense peptides were also examined. Of 42 such synthetic peptides tested in the in vitro enzyme inhibition assays using recombinant HIV protease, 13 showed inhibitory activity in the IC50 range of 0.15-3.30 mM. Hydropathically optimized anti-sense peptides generated to the flap and to the alpha helical region of the enzyme were found to be the most effective inhibitors. Complementary peptides to the catalytic site region, encompassing the Asp-Thr-Gly triad, and to the C-terminal hinge region were comparatively less inhibitory. An anti-sense peptide, generated against the gag pl7/p24 cleavage site was found to be active with an IC50 of 460 (mu)M. One example also demonstrated that an all-D amino acid containing peptide can have inhibitory properties. Efforts are focussed in designing and evaluating more effective inhibitors, and to better understand the nature of intermolecular recognition phenomenon using physicochemical methods.